The long-term goal of this proposal is to develop an effective therapy for the debilitating neurological and cognitive impairments associated with HIV-related dementia, a disorder for which there is currently no treatment. Research has provided evidence that toxins elaborated and secreted by HIV infected macrophages are responsible for the neuronal degeneration that underlies the cognitive and neurological symptoms of the disorder. Specific candidate toxins include TNF-alpha, IL-1andIL-6, quinolinate and glutamate. The mechanism of toxicity of these toxins is thought to involve the production of reactive oxygen species and neuronal cell death proceeds via an apoptotic process. This Phase II proposal builds on Phase I findings that nitrone related therapeutics (NRTs) protect against the toxic effects of these neurotoxins in in vitro and in vivo models of HIV-dementia. During Phase II we propose to (1) further evaluate the most active NRTs identified during Phase I (2) elucidate the mechanism of action of NRTs by investigating specific elements in the cascade leading to programmed cell death (3) to select the 3 most promising NRTs and optimize their dose response relationships in the animal model and (4) to evaluate potential markers of HIV dementia and therapeutic response for NRTs by studying CSF and blood specimens obtained from HIV-seropositive individuals with established mild to moderate cognitive impairment. PROPOSED COMMERCIAL APPLICATION: Approximately one third of adults and on half of children with AIDS will develop neurologic complications. If Centaur's NRTs can mitigate the effects of HIV DEMENTIA without side effects, they will represent a new type of therapy for a condition with no effective treatment. In the U.S. over 1 million individuals are infected with HIV and approximately one third of this group have AIDS. Thus, the total potential target population for an anti-HIV DEMENTIA agent is estimated currently to be greater than 100,000 patients/year. The market is expected to grow as new therapies such as the recently introduced proteinase inhibitors extend the life span of the typical AIDS patient.